Several genome wide association (GWA) studies of colorectal cancer (CRC) have been published and have reported a number of significantly associated hits that have been robustly replicated in populations of European ancestry. It is expected that the number of identified CRC associations will increase through International efforts such as those described in Areas 1 and 3 of this proposal. To date there has been only modest emphasis on characterizing the putative causal variant(s) associated with these findings and even less effort directed towards developing a comprehensive understanding of their biological relevance. Such functional studies will be necessary if we are to fully exploit the potential of GWA studies. Meeting this challenge will not be simple, as the majority of the associations identified to date through GWA studies do not target coding exons of genes, but instead target variants that lie in non-coding regions near genes or within gene-poor regions making it more difficult to determine their functional consequences. The goal of this proposal is therefore to establish a comprehensive strategy to study the biological implications of the diverse associations identified through GWA studies of CRC. We will pursue selected validated hits and novel hits identified through the proposed studies described in Areas 1 and 3 of this study. We will leverage information from state-of-the-art ChlP-seq and RNA-seq approaches and incorporate in silico methods to identify candidate causal variants in genie or regulatory regions. The functional effects of putative causal variants will be validated using comprehensive gene-specific molecular and biochemical analyses. Successful completion of our Aims should lead to a better understanding of biological mechanisms underiying genetic associations with colorectal cancer risk. The proposed study will functionally characterize new genes that predispose to colorectal cancer. This functional characterization of new genes will provide important insight into the biological mechanisms underiying genetic risk for colorectal cancer and should reveal important targets for cancer prevention and treatment